Dr. Kurella is a nephrologist and Assistant Adjunct Professor in the Department of Medicine at the University of California San Francisco. The candidate's long-term career goal is to develop an independent research career in geriatric nephrology, specifically focused on elucidating the mechanisms of cognitive impairment among elderly with end-stage renal disease (ESRD). The elderly are the fastest growing segment of the end-stage renal disease population, and the candidate's previous studies have demonstrated that the burden of cognitive impairment in this population is strikingly high and unexplained by conventional risk factors. The proposed career development plan integrates focused training in geriatrics, dementia, and neuroimaging, mentored research experience, and biostatistics training tailored to the candidate's multi-disciplinary research career plans. With the guidance of a multi-disciplinary team of mentors with expertise in dementia, geriatrics, nephrology and biostatistics, the candidate will use cognitive impairment as a model for understanding how kidney disease contributes to accelerated aging and geriatric syndromes such as dementia and disability. This proposal will (1) evaluate several metabolic and structural mechanisms of cognitive decline in ESRD by prospectively assembling a cohort of dialysis patients, and (2) test the effects of a novel dialysis therapy on cognitive function within the framework of a randomized clinical trial. The results of these studies will build incrementally on the candidate's prior research and will provide critical insight into the epidemiology and mechanisms of cognitive impairment that will guide the long-range goals of this project, a clinical trial evaluating strategies to prevent cognitive decline in elderly persons with chronic kidney disease and ESRD, to be submitted as an R01 grant application in Year 3 or 4 of the award.